It’s one of the toughest conversations imaginable: approaching a grieving family in a hospital and asking for permission to take dozens of tissues for research from a loved one who has died unexpectedly.
During the last five years, that has been the task of “tissue requesters” operating on behalf of the Genotype-Tissue Expression (GTEx) project, a $100-million effort organized by the National Institutes of Health. With the research — the first wave of which was published this month — scientists hope to illuminate the roles played by DNA variants in regulating the expression of genes. The researchers want to know how gene expression works in different parts of the same person’s body, and also in similar tissues across multiple individuals.
To do that, they must race against time, procuring tissues from subjects who have been dead for less than 12 hours — any longer, and the genetic material will have degraded so badly that it would be impossible to analyze. And the GTEx tissues must be healthy, so getting advance consent from terminally ill patients generally isn’t an option.
Hence the tough conversations. After a fatal auto accident or some other sudden event, the GTEx tissue requesters invite the next of kin to make a contribution to science, and to make that decision quickly. So far, more than 800 families have said yes.
Research on the dead occupies a regulatory gray area. Dead people aren’t considered “human subjects” for purposes of the federal Common Rule. Partly for that reason, the NIH has assembled a team of ethicists and social scientists to study the GTEx project.
The team, which is led by Laura A. Siminoff, dean of Temple University’s College of Public Health, has been interested in one question above all others: Since the families are being approached at a moment of intense grief, do they truly absorb the information they’re receiving and the consent forms they’re signing?
“These families are going through an awful lot,” Ms. Siminoff says. “They’re stressed. Their ability to recall, retain, and understand information is already compromised. So the goal is to give them critical pieces of information in such a way that will ensure that their knowledge and recall are as high as possible.”
To explore whether the requesters have succeeded, Ms. Siminoff and her colleagues have contacted the families (both those that agreed to donate and those that did not) roughly two months after their loved ones’ deaths.
It turns out that their absorption of at least one major fact about the study has been far from perfect. At least 40 percent of the respondents did not understand that the GTEx researchers will never return personalized information about genetic findings that may affect donors’ families — say, a predisposition to ovarian cancer or cardiac dysrhythmias.
(Almost all of the families — more than 90 percent — said they would like such information in cases where the diseases are treatable or preventable.)
‘Fairly Damning’
That finding, which Ms. Siminoff and her colleagues reported in a paper in April in the journal Genetics in Medicine, strikes some scholars as disheartening or worse. A basic principle of informed consent is that participants should understand the potential risks and benefits — and here is evidence that many GTEx donors have overestimated the personal benefits they might receive.
“It’s really fairly damning,” says Henry T. Greely, a law professor at Stanford University who has written widely about the ethics of genetic research.
In GTEx and in biomedical research of all kinds, Mr. Greely says, “we need to work much harder to make sure that people really understand what they’re signing. But that will run up against a constant tension. The more candid and honest you are with potential research subjects, or in this case the next of kin, the more likely they are to say no.”
Ms. Siminoff, however, denies that such tension is really so inevitable. With the correct training, she says, tissue requesters can improve both their acceptance rates and the donor families’ comprehension of what they’re signing up for.
Already, she says, the findings in her study have been used to revise the requesters’ training and the printed information that potential donors receive. In future publications, she intends to explore whether those changes have improved more-recent donor families’ understanding of the research.
It still is not clear, Ms. Siminoff adds, whether the families’ imperfect understanding is a product of their grief and distraction when they were told about the research. Perhaps it is mostly a simple matter of the frailty of human memory.
To test that question, Ms. Siminoff and her colleagues are running mock requests with nongrieving families, and recontacting them two months later to assess their memories of the earlier interaction.
The researchers initially considered procuring tissues from patients undergoing certain surgeries, but only a very few specimens were actually ever collected from living subjects, according to Nicole C. Lockhart, a health-sciences administrator at the National Human Genome Research Institute, which is part of the NIH. The project prefers to obtain samples of a variety of tissue types from the same individual — heart, brain, liver, blood, skin, and so on — which generally means that collecting them from living subjects would be unreasonably dangerous.
The vast majority of specimens have come from people who have unexpectedly died. In most cases, the subjects were already on organ-donor registries. In every case, collecting organs for transplant takes priority over collecting them for research. So a subject might, say, give a kidney to a patient in renal failure and simultaneously have a dozen other tissue types extracted for the GTEx project.
Mr. Greely, who has no affiliation with GTEx, says that it’s to the NIH’s credit that Ms. Siminoff’s team has been given so much scope to ask searching questions about the quality of the informed-consent process. He adds, however, that no one should feel it’s acceptable to have such poor comprehension among research participants and donors.
“Business as usual in biomedical research,” he says, “is to let people be deceived about what’s happening, or to let people deceive themselves. That’s very problematic.”
‘Incidental Findings’
Moreover, Mr. Greely adds, the GTEx project ought to change its policy to align more with what happens in the clinical world.
“If you take a chest X-ray to look for lung cancer and you don’t see lung cancer but you do see an aortic aneurysm, you tell the patient,” he says. Not in the GTEx project — though the American College of Medical Genetics and Genomics has compiled a list of 56 disease-associated genetic variants that patients and research participants should be notified of.
“Only in genetic research is there this reluctance to share incidental findings,” says Mr. Greely. If he were a GTEx family donor, he says, he would be unhappy to know that the researchers might be sitting on highly pertinent information about the family’s health.
The architects of GTEx decided not to return incidental findings for several reasons, Ms. Lockhart says. For one thing, a family’s decision maker who authorizes a GTEx donation is often a spouse, which means that she or he wouldn’t be directly affected by any genetic predispositions that might be discovered. Contacting additional family members might be legally and logistically complicated.
Nonetheless, she adds, “the debate about incidental findings has changed a great deal since we started GTEx, in 2010. If we were beginning today, we might have had a different approach.”
Ms. Siminoff agrees that future large-scale genetic studies should strongly consider returning incidental findings, since almost all donor families seem to want them.
Meanwhile, she is focusing on her task of improving the work done by the GTEx tissue requesters.
“Those requesters have an unbelievably stressful job,” she says. “I don’t think people really quite appreciate how stressful organ procurement is. The more skills we can give people, the better they can do their jobs. That’s why I’ve been so glad to work on this study.”
